Targeting nanotherapeutics against murine and feline oral cancer Abstract: This is a competitive renewal proposal of our R01 EB012569 grant. Through the R01 support, we have recently developed an exciting nanoplatform, which we believe will be an excellent subject for this competitive R01 renewal. This novel multifunctional porphyrin-based micellar nanoplatform, recently published in Nature Communication (August 2014), allows (i) efficient encapsulation of hydrophobic chemotherapeutic drugs or hsp90 inhibitor, (ii) near-infra red fluorescent (NIRF) detection of the tumor based on the intrinsic fluorescence of porphyrins and/or encapsulated cyanine dye, (iii) efficient free radical and heat generation at tumor site upon activation with light for photodynamic therapy (PDT) and photothermal therapy (PTT), respectively, (iv) convenient ligation of cancer-targeting ligands to the surface of the micelle for cancer-specific targeted delivery, and (v) chelation of Gd (III) or 64Cu for MRI and PET imaging, respectively. We have shown that nanoporphyrin-mediated PDT led to significant tumor inhibition by using much lower dose of light and photosensitizer compared with the recently reported porphyrin formulations, e.g. liposomal porphyrins. Furthermore, the nanoporphyrin-mediated combination chemotherapy and PDT (Chemo-PDT) was dramatically more efficacious than single treatment alone. This novel PDT agent is far superior than existing FDA approved photosensitizer. We therefore would like to develop this agent for the treatment of oral cancers, which is readily accessible to illumination with near infrared light (NIRL). We will use both xenograft model and spontaneous oral cancer in companion cat to evaluate this novel nanotheranostic agent. The 4 specific aims are: Aim 1. To design and synthesize porphyrin/cyanine dye derivatives and use them to prepare various hybrid telodendrimers suitable for the construction of micelle-based porphyrin nanoparticles called nanoporphyrins (NP). Aim 2. To use optical and MR imaging to determine the biodistribution and OSCC targeting properties of targeting-crosslinked NPs (CNPs) from aim 1, using orthotopically implanted luciferase-transfected OSCC xenograft models. Aim 3. To determine the in vivo toxicity and anti-tumor efficacy of the doxorubicin/17AAG-loaded targeting-CNPs optimized in aim 2. Aim 4. To use companion cat with spontaneous oral cancer as a model system to (i) determine the biodistribution and tumor uptake of targeting-CNP using optical imaging and MRI scan, (ii) perform pharmacokinetic and pharmacodynamics studies of CNP, and (iii) perform a Phase I clinical trial of phototherapy of drug-loaded targeting CNP. Innovation and Impact Our crosslinked nanoporphyrin (CNP) can (i) afford multimodality imaging (near- infra red fluorescent, MRI, PET, and SPECT), and quadruple whammy against targeted tumor (PDT, PTT, chemotherapy and Hsp90 inhibitor), (ii) reach even very small metastatic tumor cell cluster (50-100 m), and (iii) take advantage of the tumor ligand LLS13 that we have already identified for enhancing intracellular uptake. Papilloma virus associated oropharyngeal cancer is on the rise in the United States3. It is one of the few cancers that are accessible to illumination with light, making it an ideal tumor type that can greatly benefit from this novel photo-theranostic agent for both detection and elimination of the disease.